Bone degenerative diseases such as osteoporosis occur in a substantial portion of the senior adult population. Osteoporosis encompasses a heterogeneous group of disorders that represent a major risk for bone fractures, and a substantial burden on the health care system. Billions of dollars are spent annually on medical care for the treatment of osteoporosis. Clinically, osteoporosis is characterized by diminished bone mass, decreased bone mineral density (BMD) and bone mineral content (BMC), and loss of bone architecture resulting in decreased bone strength and increased risk of bone fracture.
While a number of antiresorptive agents including calcitonin, bisphosphonates, estrogen, and SERMs prevent further bone loss, they do not rebuild bone once it has been lost. The first FDA approved anabolic bone building agent for the treatment of osteoporosis is human PTH(1-34), also known as teriparatide, which is marketed under the brand name FORTEO® (Eli Lilly and Company, Indianapolis, Ind.). PTH or PTH(1-34) is thought to exert its effects through receptor-mediated activation of two intracellular signaling pathways via (1) adenylate cyclase and protein kinase A, and (2) phospholipase C and protein kinase C. PTH(1-34) builds bone mass, restores bone architecture, and reduces the risk of vertebral and non-vertebral bone fractures in osteoporotic patients who are at high risk of fracture. (R. Neer, NEJM, 344:1434, 2001). As a peptide product, PTH(1-34) requires daily subcutaneous injections. International Publication Number WO2004/060386 discloses an enormous genus of PTH/PTHrP modulators comprising a vehicle that cause greater hypercalcemic response than PTH(1-34).
There remains a need for novel, therapeutic PTH analogs that demonstrate bone building efficacy as reflected by increased bone mineral content (BMC) and/or bone strength while preferably maintaining a hypercalcemia effect similar to, or less than, that of the current PTH(1-34) therapeutic and which requires less frequent administration than PTH(1-34). The compounds of the present invention satisfy these needs and provide related advantages.